发现4-氮杂吲哚作为免疫肿瘤药物对转化生长因子β受体I（TGFβRI）的抑制剂
Discovery of 4-Azaindole Inhibitors of TGFβRI as Immuno-oncology Agents.
作者信息
Zhang Yong, Zhao Yufen, Tebben Andrew J, Sheriff Steven, Ruzanov Max, Fereshteh Mark P, Fan Yi, Lippy Jonathan, Swanson Jesse, Ho Ching-Ping, Wautlet Barri S, Rose Anne, Parrish Karen, Yang Zheng, Donnell Andrew F, Zhang Liping, Fink Brian E, Vite Gregory D, Augustine-Rauch Karen, Fargnoli Joseph, Borzilleri Robert M
机构信息
Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, New Jersey 08543, United States.
出版信息
ACS Med Chem Lett. 2018 Oct 17;9(11):1117-1122. doi: 10.1021/acsmedchemlett.8b00357. eCollection 2018 Nov 8.
Abstract
The multifunctional cytokine TGFβ plays a central role in regulating antitumor immunity. It has been postulated that inhibition of TGFβ signaling in concert with checkpoint blockade will provide improved and durable immune response against tumors. Herein, we describe a novel series of 4-azaindole TGFβ receptor kinase inhibitors with excellent selectivity for TGFβ receptor 1 kinase. The combination of compound and an antimouse-PD-1 antibody demonstrated significantly improved antitumor efficacy compared to either treatment alone in a murine tumor model.
摘要
多功能细胞因子转化生长因子β（TGFβ）在调节抗肿瘤免疫中起核心作用。据推测，与检查点阻断协同抑制TGFβ信号传导将产生针对肿瘤的更强且持久的免疫反应。在此，我们描述了一系列新型的4-氮杂吲哚TGFβ受体激酶抑制剂，它们对TGFβ受体1激酶具有优异的选择性。在小鼠肿瘤模型中，化合物与抗小鼠程序性死亡蛋白1（PD-1）抗体联合使用时，与单独使用任何一种治疗方法相比，均显示出显著提高的抗肿瘤疗效。
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